The esophageal lining is regularly exposed to irritants such as alcohol, cigarette smoke, hot beverages, dietary nitroso-compounds, and refluxate of gastro-duodenal contents, and disorders of the esophagus are significant health problems in the U.S. and throughout the world. For example, gastroesophageal reflux disease (GERD) leads to 8.9 million U.S. clinic visits annually, and esophageal cancer is the 6th most common cause of cancer death worldwide. In esophageal epithelia, the key transcriptional regulator Krppel-like factor 5 (KLF5) promotes normal proliferation and migration, as we have shown, and we recently identified a novel relationship between KLF5 and p53 in esophageal epithelial cells, whereby p53 acts as a molecular switch for KLF5. p53 mutation in primary human esophageal keratinocytes converts KLF5 from pro-proliferative to anti-proliferative, an effect mediated predominantly by p21Waf1/Cip1, and KLF5 transcriptionally activates the keratinocyte tumor suppressor NOTCH1 when p53 is mutant but not with wild-type p53. In additional Preliminary Data, we demonstrate that KLF5 suppresses p53 in esophageal keratinocytes and provide evidence for genome-wide coordinate regulation by KLF5 and p53. Our overarching hypothesis is that KLF5 and p53 orchestrate a broad transcriptional program in esophageal keratinocytes that controls proliferation, growth arrest, apoptosis, and transformation. To test this hypothesis, we will pursue the following interrelated Specific Aims: 1. We will delineate the mechanisms through which KLF5 regulates p53 levels and function~ 2. We will define the mechanism for KLF5 functional switching on p21Waf1/Cip1~ 3. We will identify common and exclusive targets of KLF5 in the context of wild-type and mutant p53~ and 4. We will determine the functional consequences of KLF5 loss and p53 mutation in vivo. These complementary approaches are supported by our robust Preliminary Data, both published and unpublished. Moreover, the PI is an experienced investigator who is an expert in the Krppel-like factors (KLFs), transcriptional regulation, animal models of gastrointestinal diseases, and esophageal squamous cell biology, as demonstrated by recent, relevant corresponding-author publications in Cancer Research, PLoS One, Cell Cycle, and Neoplasia. In addition, the PI is supported by a superb research team, complemented by expert collaborators, and by the exceptional resources, facilities, and intellectual environment of the University of Pennsylvania and the NIH-funded Center for Molecular Studies in Digestive and Liver Diseases. Overall, the proposed studies will provide key insights into the transcriptional regulation of esophageal epithelial homeostasis and the molecular pathways that underlie esophageal diseases, both benign and malignant.